Enteropathic arthritis (also known as enteroarthritis) is a spondyloarthritis which occurs in patients with gastrointestinal diseases, such as, inflammatory bowel diseases (IBDs) and other diseases, such as, for example, Whipple's disease, celiac disease, and disorders resulting from intestinal bypass surgery (e.g., jejunoileal bypass). (Orlando et al., “Gastrointestinal lesions associated with spondyloarthropathies,” World Journal of Gastroenterology, 15(20):2443-2448 (2009).)
Spondyloarthritis is typically classified into two subsets: axial spondyloarthritis and peripheral spondyloarthritis. Subcategories of axial spondyloarthritis are i. ankylosing spondylitis (also known as radiographic axial spondyloarthritis) and ii. non-radiographic axial spondyloarthritis. Axial spondyloarthritis is characterized by long-term inflammation of the joints of the spine, sometimes also including the joints where the spine joins the pelvis. Peripheral spondyloarthritis is characterized by inflammation of the joints in the arms and legs, most often the lower legs.
Attacks or flares of the joint inflammation are typical in both forms of spondyloarthritis. These flares usually have a rapid onset, typically setting in within 48 hours. The flares sometimes disappear within about six months, but inflammation can become chronic in some people. The symptoms of gastrointestinal diseases sometimes flare along with the symptoms of spondyloarthritis in enteropathic arthritis.
Inflammatory bowel diseases involve chronic inflammation of the digestive tract. The most common forms of IBD are ulcerative colitis (UC) and Crohn's disease (CD). Ulcerative colitis is characterized by inflammation and sores in the inner lining of the large intestine (colon) and rectum. Crohn's disease is characterized by inflammation anywhere in the digestive tract (including both the small and large intestines) and can spread deeper into the tissues. Less severe forms of IBDs include collagenous colitis and lymphocytic colitis. Symptoms of IBD include abdominal pain, diarrhea, weight loss, hematochezia, tenesmus, fever and nutritional deficiencies Inflammatory bowel diseases can be devastating and can lead to life-threatening complications.
Currently, it is beneficial if the management of patients with enteropathic arthritis involves an active cooperation between gastroenterologist and rheumatologist.
Treatment of enteropathic arthritis includes the use of disease-modifying anti-rheumatic drugs (DMARDs), anti-TNFα agents, and immunosuppressants (e.g., corticosteroids, methotrexate, azathioprine, cyclosporine, and leflunomide). However, these pharmaceuticals have varying degrees of efficacy in one of both components of enteropathic arthritis. For example, some anti-TNFα agents, especially infliximab and adalimumab, have been successful in treating both the intestinal inflammation and the joint pain in patients with enteropathic arthritis, especially in patients with the CD component; however, etanercept is effective only to control joint symptoms, i.e., not gastrointestinal symptoms. Further, most of the current pharmaceutical treatments tend to have significant adverse effects.
Additionally, sulfasalazine and 5-aminosalicylic acid are often used for the treatment of UC, and their effectiveness has also been shown for the management of mild peripheral arthritis. However, their effectiveness on CD is still questionable. Further, these drugs have no effect on the progression of joint damage and their usefulness in the axial subset is marginal; and they do not seem to prevent the onset of gastrointestinal inflammation.
It has been reported that patients may respond to anti-inflammatory drugs, useful to control joint inflammation. However, such drugs may exacerbate IBD (Kaufmann et al., “NSAIDs activate quiescent inflammatory bowel disease,” Annals of Internal Medicine. 107(4):513-516 (1987); Bjarnason et al., “Side effects of NSAIDs on the small and large intestine in humans,” Gastroenterology. 104(6):1832-1847 (1993)). For example, nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to cause the appearance of small intestine and colon ulcers (Kaufman et al., “Colonic ulceration associated with NSAIDs: report of three cases,” Diseases of the Colon and Rectum. 39(6):705-710 (1996)). As a consequence, in order to manage joint symptoms, NSAIDs may be recommended only for patients who experience mild exacerbations of gastrointestinal distress; and even then, NSAID use should be limited to the lowest effective dose and only for short periods of time.
In fact, the main factor limiting NSAID use in any ailment is the concern for the development of gastrointestinal toxicity including mucosal injury in the form of erosions and ulcers; upper gastrointestinal (GI), small bowel or colonic bleeding; and sometimes perforation and obstruction due to stricture formation (Wolfe et al., “Gastrointestinal toxicity of NSAIDs.” N. Engl. J. Med. 340:1888-1899 (1999)). NSAIDs may also cause a nonspecific type of colitis and small intestinal inflammation with associated complications of chronic blood or protein loss (Bjarnason et al., Gastroenterology. 104:1832-1847 (1993)). Endoscopic features of NSAID-induced colonic damage include sharply demarcated or circumferential ulcers which are usually reversible upon discontinuation of the drug (Kurahara et al., “Clinical and endoscopic features of NSAID-induced colonic ulcerations.” Am. J. Gastroenterol. 96:473-480 (2001)). It is estimated that NSAID use by patients with arthritis in the United States causes over 100,000 hospitalizations annually for GI complications, one fifth of which are estimated to be due to lower GI complications (Laine et al., “Systematic review: the lower gastrointestinal adverse effects of NSAIDs.” Aliment Pharmacol. Ther. 24:751-767 (2006)). A review of the literature of lower GI adverse effects of NSAIDs revealed that there was a statistically significant increase in adverse outcome rates associated with the use of NSAIDs in patients with lower GI bleeding, perforation and complicated diverticular disease (Guslandi M. “Exacerbation of inflammatory bowel disease by NSAIDs and cyclooxygenase-2 inhibitors: fact or fiction?” World J. Gastroenterol.12:1509-1510 (2006)).
Further, it has been found that NSAID use may initiate IBD, or cause reactivation of quiescent disease and induce GI complications (Fries et al., “Toward an epidemiology of gastropathy associated with NSAID use.” Gastroenterology. 96(Suppl.):647-655 (1996)). Several studies have implicated NSAID use in the onset or exacerbation of IBD (Singh et al., “Do NSAIDs, antibiotics, infections, or stress trigger flares in IBD?” Am. J. Gastroenterol. 104:1298-1313 (2009); Felder et al., “Effects of NSAIDs on IBD: a case-control study.” Am. J. Gastroenterol. 95:1949-1954 (2000)). Using clinical evaluation and fecal calprotectin measurements, it was demonstrated that non-selective NSAIDs were associated with a 17-28% relapse rate within nine days of ingestion of the drug, in patients with IBD (Takeuchi et al., “Prevalence and mechanism of NSAID-induced clinical relapse in patients with inflammatory bowel disease.” Clin. Gastroenterol Hepatol. 4:196-202 (2006)). Also, retrospectively reviewed files of outpatients with IBD showed that treatment with NSAIDs was associated with disease relapse (Meyer et al., “Relapse of IBD associated with use of NSAIDs.” Dig. Dis. Sci. 51:168-172 (2006)). Thus, plainly, the use of NSAIDs in patients with diseases that have a gastrointestinal component, such as enteropathic arthritis, is generally contraindicated.
Clearly, there is a need for a more effective and accessible manner by which to treat individuals with enteropathic arthritis.